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Abstract: fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive, extensive, and irreversible heterotopic ossification (HO) of soft tissues throughout the body, leading to severe disabilities. FOP is caused primarily by mutations in activin A receptor type 1 (ACVR1), also known as activin-like kinase 2 (ALK2), which encodes a receptor belonging to the bone morphogenetic protein (BMP) type I family. However, the continuous and complex process of HO in FOP is not yet fully understood, which has impeded the development of therapeutic drugs. Despite surgical removal of HO, which often results in recurrence and expansion of ossification, there is currently no definitive drug treatment available to completely prevent, halt, or reverse the progression of HO in FOP. Currently, researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates, including saracatinib, palovarotene, and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs, with the goal of providing insights for further research and the development of new treatment methods.

进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展

[1]AykulS,CorpinaRA,GoebelEJ,et al.,2020.Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.eLife,9:e54582.

[2]AykulS,HuangL,WangLL,et al.,2022.Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.J Clin Invest,132(12):e153792.

[3]BabikerHM,ByronSA,HendricksWPD,et al.,2019.E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases.Invest New Drugs,37(4):636-645.

[4]BarruetE,MoralesBM,CainCJ,et al.,2018.NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification.JCI Insight,3(22):e122958.

[5]Blueprint Medicines Corporation,2019.Safety, tolerability, pharmacokinetics, and food effect of BLU-782 in healthy adults.ClinicalTrials.gov ID NCT03858075.https://clinicaltrials.gov/study/NCT03858075

[6]BrennanTA,LindborgCM,BergbauerCR,et al.,2018.Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP).Bone,109:259-266.

[7]CaiJ,OrlovaVV,CaiX,et al.,2015.Induced pluripotent stem cells to model human fibrodysplasia ossificans progressiva.Stem Cell Rep,5(6):963-970.

[8]CapdevilleR,BuchdungerE,ZimmermannJ,et al.,2002.Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug.Nat Rev Drug Discov,1(7):493-502.

[9]ChaikuadA,AlfanoI,KerrG,et al.,2012.Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.J Biol Chem,287(44):36990-36998.

[10]ChakkalakalSA,UchibeK,ConventeMR,et al.,2016.Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the humanACVR1^R206H fibrodysplasia ossificans progressiva (FOP) mutation.J Bone Miner Res,31(9):1666-1675.

[11]ChenYY,StubbsMC,PuseyM,et al.,2020.Characterization of INCB00928, a potent and selective ALK2 inhibitor for the treatment of anemia.Blood,136(Suppl 1):52.

[12]ChiuW,LinTY,ChangYC,et al.,2021.An update on gene therapy for inherited retinal dystrophy: experience in leber congenital amaurosis clinical trials.Int J Mol Sci,22(9):4534.

[13]ConventeMR,ChakkalakalSA,YangEJ,et al.,2018.Depletion of mast cells and macrophages impairs heterotopic ossification in anAcvr1^R206H mouse model of fibrodysplasia ossificans progressiva.J Bone Miner Res,33(2):269-282.

[14]CunyGD,YuPB,LahaJK,et al.,2008.Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.Bioorg Med Chem Lett,18(15):4388-4392.

[15]de RuiterR,GrootT,SchoenmakerT,et al.,2022.Fibroblasts from patients with fibrodysplasia ossificans progressiva exhibit increased activin a production.J Bone Miner Res,37:320-320.

[16]de RuiterRD,WisseLE,SchoenmakerT,et al.,2023.TGF-beta induces activin a production in dermal fibroblasts derived from patients with fibrodysplasia ossificans progressiva.Int J Mol Sci,24(3):2299.

[17]del ZottoG,AntoniniF,AzzariI,et al.,2018.Peripheral blood mononuclear cell immunophenotyping in fibrodysplasia ossificans progressiva patients: evidence for monocyte DNAM1 up‐regulation.Cytometry B Clin Cytom,94(4):613-622.

[18]DeyD,BagarovaJ,HatsellSJ,et al.,2016.Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification.Sci Transl Med,8(366):366ra163.

[19]EngersDW,FristAY,LindsleyCW,et al.,2013.Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe.Bioorg Med Chem Lett,23(11):3248-3252.

[20]EngersDW,BollingerSR,FeltsAS,et al.,2020.Discovery, synthesis and characterization of a series of 7-aryl-imidazo[1,2-a]pyridine-3-ylquinolines as activin-like kinase (ALK) inhibitors.Bioorg Med Chem Lett,30(18):127418.

[21]FortinJ,TianRX,ZarrabiI,et al.,2020.MutantACVR1 arrests glial cell differentiation to drive tumorigenesis in pediatric gliomas.Cancer Cell,37(3):308-323.e12.

[22]GámezB,Rodríguez-CarballoE,GrauperaM,et al.,2016.Class I PI-3-kinase signaling is critical for bone formation through regulation of SMAD1 activity in osteoblasts.J Bone Miner Res,31(8):1617-1630.

[23]HannonRA,ClackG,RimmerM,et al.,2010.Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial.J Bone Miner Res,25(3):463-471.

[24]HaoJJ,HoJN,LewisJA,et al.,2010.In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors.ACS Chem Biol,5(2):245-253.

[25]HatsellSJ,IdoneV,WolkenDMA,et al.,2015.ACVR1^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A.Sci Transl Med,7(303):303ra137.

[26]HavivR,MosheV,de BenedettiF,et al.,2019.Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome?Pediatr Rheumatol,17:84.

[27]HennequinLF,AllenJ,BreedJ,et al.,2006.N-(5-Chloro-1,3-benzodioxol-4-yl)‍-7-‍[2-‍(4-methylpiperazin-1-yl)ethoxy]‍-5-

[28]tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine,novela,selectivehighly,availableorally,dual-specific c-Src/Abl kinase inhibitor.J Med Chem,49(22):6465-6488.

[29]HerbertKE,WalkleyCR,WinklerIG,et al.,2007.Granulocyte colony-stimulating factor and an RARα specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells.Transplantation,83(4):375-384.

[30]HildebrandtS,KampfrathB,FischerK,et al.,2021.Activina induced SMAD1/5 signaling in an iPSC derived EC model of fibrodysplasia ossificans progressiva (FOP) can be rescued by the drug candidate saracatinib.Stem Cell Rev Rep,17(3):1039-1052.

[31]HinoK,HorigomeK,NishioM,et al.,2017.Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva.J Clin Invest,127(9):3339-3352.

[32]HinoK,ZhaoCZ,HorigomeK,et al.,2018.An mTOR signaling modulator suppressed heterotopic ossification of fibrodysplasia ossificans progressiva.Stem Cell Rep,11(5):1106-1119.

[33]HochhausA,LarsonRA,GuilhotF,et al.,2017.Long-term outcomes of imatinib treatment for chronic myeloid leukemia.N Engl J Med,376(10):917-927.

[34]HrkacS,NovakR,SalaiG,et al.,2022.Heterotopic ossification vs. fracture healing: extracellular vesicle cargo proteins shed new light on bone formation.Bone Rep,16:101177.

[35]HuY,HaoXQ,LiuCW,et al.,2021.Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis.J Cell Physiol,236(6):4580-4591.

[36]HwangC,MariniS,HuberAK,et al.,2019.Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.Bone Res,7:36.

[37]HwangCD,PaganiCA,NunezJH,et al.,2022.Contemporary perspectives on heterotopic ossification.JCI Insight,7(14):e158996.

[38]IFOPA,2022.DS-6016a.https://www.ifopa.org/ds_6016a

[39]CorporationIncyte,2024.To assess the efficacy, safety, and tolerability of INCB000928 in participants with fibrodysplasia ossificans progressiva (progress).ClinicalTrials.gov ID NCT05090891.https://clinicaltrials.gov/study/NCT05090891

[40]JacobsenKL,WiebeV,DavidsonAP,et al.,2023.Use of enrofloxacin and hydrotherapy in the management of fibrodysplasia ossificans progressiva (FOP) in a Savannah cat.Top Companion Anim Med,52:100757.

[41]JiaSJ,MengAM,2021.TGFβ family signaling and development.Development,148(5):dev188490.

[42]JiangJK,HuangXL,ShamimK,et al.,2018.Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,‍5-a]pyrimidines as potent and selective ALK2 inhibitors.Bioorg Med Chem Lett,28(20):3356-3362.

[43]KaplanFS,AndolinaJR,AdamsonPC,et al.,2018a.Early clinical observations on the use of imatinib mesylate in FOP: a report of seven cases.Bone,109:276-280.

[44]KaplanFS,ZeitlinL,DunnSP,et al.,2018b.Acute and chronic rapamycin use in patients with fibrodysplasia ossificans progressiva: a report of two cases.Bone,109:281-284.

[45]KaplanJ,KaplanFS,ShoreEM,2012.Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting.Gene Ther,19(7):786-790.

[46]KatagiriT,TsukamotoS,KurataniM,et al.,2023.A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders.Nat Commun,14:2960.

[47]KawamataM,SuzukiHI,KimuraR,et al.,2023.Optimization of Cas9 activity through the addition of cytosine extensions to single-guide RNAs.Nat Biomed Eng,7(5):672-691.

[48]KitohH,2020.Clinical aspects and current therapeutic approaches for FOP.Biomedicines,8(9):325.

[49]Lees-ShepardJB,StoesselSJ,ChandlerJT,et al.,2022.An anti-ACVR1 antibody exacerbates heterot ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice.J Clinical Invest,132(12):e153795.

[50]LimKH,HanZ,JeonHY,et al.,2020.Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression.Nat Commun,11:3501.

[51]LuoY,AlsamarahA,ZhangK,et al.,2016.Development of new therapeutic agents for fibrodysplasia ossificans progressiva.Curr Mol Med,16(1):4-11.

[52]MaoD,MiJY,PanXY,et al.,2022.Galunisertib attenuates progression of trauma-induced heterotopic ossification via blockage of Smad2/3 signaling in mice.Eur J Pharmacol,928:175109.

[53]MaruyamaR,YokotaT,2018.Morpholino-mediated exon skipping targeting human ACVR1/ALK2 for fibrodysplasia ossificans progressiva. In: Yokota T, Maruyama R (Eds.),Exon Skipping and Inclusion Therapies: Methods and Protocols.Humana Press,New York, p.497-502.

[54]MaruyamaR,NguyenQ,RoshmiRR,et al.,2022.Allele-selective LNA gapmers for the treatment of fibrodysplasia ossificans progressiva knock down the pathogenic ACVR1^R206H transcript and inhibit osteogenic differentiation.Nucl Acid Ther,32(3):185-193.

[55]MengXM,WangHT,HaoJJ,2022.Recent progress in drug development for fibrodysplasia ossificans progressiva.Mol Cell Biochem,477(10):2327-2334.

[56]MohedasAH,XingXC,ArmstrongKA,et al.,2013.Development of an ALK2-biased BMP type I receptor kinase inhibitor.ACS Chem Biol,8(6):1291-1302.

[57]NagarG,MittalP,GuptaSRR,et al.,2023.Multi-omics therapeutic perspective on ACVR1 gene: from genetic alterations to potential targeting.Brief Funct Genomics,22(2):123-142.

[58]NguyenMH,AtasoyluO,WuLX,et al.,2022.Discovery of novel pyrazolopyrimidines as potent, selective, and orally bioavailable inhibitors of ALK2.ACS Med Chem Lett,13(7):1159-1164.

[59]NikishinaIP,ArsenyevaSV,MatkavaVG,et al.,2023.Successful experience of tofacitinib treatment in patients with fibrodysplasia ossificans progressiva.Pediatr Rheumatol,21:92.

[60]OhteS,YamazakiH,TakahashiO,et al.,2021.Inhibitory effects of sesquiterpene lactones from the indonesian marine spongeLamellodysidea cf.herbacea on bone morphogenetic protein-induced osteoblastic differentiation.Bioorg Med Chem Lett,35:127783.

[61]PacificiM,2018.Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial.Bone,109:267-275.

[62]PierceJL,PerrienDS,2021.Do interactions of vitamin D₃ and BMP signaling hold implications in the pathogenesis of fibrodysplasia ossificans progressiva?Curr Osteoporos Rep,19(3):358-367.

[63]PignoloRJ,PacificiM,2021.Retinoid agonists in the targeting of heterotopic ossification.Cells,10(11):3245.

[64]PignoloRJ,WangHT,KaplanFS,2020.Fibrodysplasia ossificans progressiva (FOP): a segmental progeroid syndrome.Front Endocrinol,10:908.

[65]PignoloRJ,Bedford-GayC,CaliA,et al.,2022a.Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective.Orphanet J Rare Dis,17:168.

[66]PignoloRJ,McCarrick‐‍WalmsleyR,WangHT,et al.,2022b.Plasma‍‐‍soluble biomarkers for fibrodysplasia ossificans progressiva (FOP) reflect acute and chronic inflammatory states.J Bone Miner Res,37(3):475-483.

[67]PignoloRJ,HsiaoEC,al MukaddamM,et al.,2023.Reduction of new heterotopic ossification (HO) in the open‐label, phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP).J Bone Miner Res,38(3):381-394.

[68]QureshiAT,DeyD,SandersEM,et al.,2017.Inhibition of mammalian target of rapamycin signaling with rapamycin prevents trauma-induced heterotopic ossification.Am J Pathol,187(11):2536-2545.

[69]RugoHS,AndréF,YamashitaT,et al.,2020.Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.Ann Oncol,31(8):1001-1010.

[70]Sánchez-DuffhuesG,WilliamsE,BenderitterP,et al.,2019.Development of macrocycle kinase inhibitors for ALK2 using fibrodysplasia ossificans progressiva-derived endothelial cells.JBMR Plus,3(11):e10230.

[71]SanvitaleCE,KerrG,ChaikuadA,et al.,2013.A new class of small molecule inhibitor of BMP signaling.PLoS ONE,8(4):e62721.

[72]SatoT,SekimataK,SakaiN,et al.,2020.Structural basis of activin receptor-like kinase 2 (R206H) inhibition by bis-heteroaryl pyrazole-based inhibitors for the treatment of fibrodysplasia ossificans progressiva identified by the integration of ligand-based and structure-based drug design approaches.ACS Omega,5(20):11411-11423.

[73]SchoenmakerT,ZwaakJ,LoosBG,et al.,2023.Transcriptomic differences underlying the activin-A induced large osteoclast formation in both healthy control and fibrodysplasia ossificans progressiva osteoclasts.Int J Mole Sci,24(7):6822.

[74]SheDM,ZhangKQ,2018.Fibrodysplasia ossificans progressiva in China.Bone,109:101-103.

[75]ShiST,CaiJ,de GorterDJJ,et al.,2013.Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.PLoS ONE,8(7):e69096.

[76]ShimonoK,MorrisonTN,TungWE,et al.,2010.Inhibition of ectopic bone formation by a selective retinoic acid receptor α-agonist: a new therapy for heterotopic ossification?J Orthop Res,28(2):271-277.

[77]ShimonoK,TungWE,MacolinoC,et al.,2011.Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists.Nat Med,17(4):454-460.

[78]ShoreEM,XuMQ,FeldmanGJ,et al.,2006.A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.Nat Genet,38(5):525-527.

[79]SmildeBJ,BotmanE,de RuiterR,et al.,2022.Monitoring and management of fibrodysplasia ossificans progressiva: current perspectives.Orthop Res Rev,14:113-120.

[80]SongGA,KimHJ,WooKM,et al.,2010.Molecular consequences of the ACVR1^R206H mutation of fibrodysplasia ossificans progressiva.J Biol Chem,285(29):22542-22553.

[81]StanleyA,TichyED,KocanJ,et al.,2022.Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva.npj Regen Med,7:5.

[82]StrongAL,SpreadboroughPJ,PaganiCA,et al.,2020.Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma.Bone,139:115517.

[83]TironeM,GiovenzanaA,ValloneA,et al.,2019.Severe heterotopic ossification in the skeletal muscle and endothelial cells recruitment to chondrogenesis are enhanced by monocyte/macrophage depletion.Front Immunol,10:1640.

[84]TowlerOW,ShoreEM,2022.BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP).Dev Dyn,251(1):144-157.

[85]UllrichT,AristaL,WeilerS,et al.,2022.Discovery of a novel 2-aminopyrazine-3-carboxamide as a potent and selective inhibitor of activin receptor-like kinase-2 (ALK2) for the treatment of fibrodysplasia ossificans progressiva.Bioorg Med Chem Lett,64:128667.

[86]UpadhyayJ,XieLQ,HuangL,et al.,2017.The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin A-dependent.J Bone Miner Res,32(12):2489-2499.

[87]ValerJA,Sánchez-de-DiegoC,GámezB,et al.,2019.Inhibition of phosphatidylinositol 3-kinase α (PI3α) prevents heterotopic ossification.EMBO Mol Med,11(9):e10567.

[88]VenturaF,WilliamsE,IkeyaM,et al.,2021.Challenges and opportunities for drug repositioning in fibrodysplasia ossificans progressiva.Biomedicines,9(2):213.

[89]WangHT,LindborgC,LounevV,et al.,2016.Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling.J Bone Miner Res,31(9):1652-1665.

[90]WangHT,de CuntoCL,PignoloRJ,et al.,2021.Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients.Bone,149:115978.

[91]WangHT,ZhangQ,KaplanFS,et al.,2022.Clearance of senescent cells from injured muscle abrogates heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva.J Bone Miner Res,37(1):95-107.

[92]WareAD,BrewerN,MeyersC,et al.,2019.Differential vascularity in genetic and nonhereditary heterotopic ossification.Int J Surg Pathol,27(8):859-867.

[93]WentworthKL,MasharaniU,HsiaoEC,2019.Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.Br J Clin Pharmacol,85(6):1180-1187.

[94]WentworthKL,LalondeRL,GroppeJC,et al.,2022.Functional testing of bone morphogenetic protein (BMP) pathway variants identified on whole‐exome sequencing in a patient with delayed‐onset fibrodysplasia ossificans progressiva (FOP) using ACVR1^R206H‐specific human cellular and zebrafish models.J Bone Miner Res,37(11):2058-2076.

[95]WestonAD,HoffmanLM,UnderhillTM,2003.Revisiting the role of retinoid signaling in skeletal development.Birth Defects Res Part C Embryo Today,69(2):156-173.

[96]WilliamsE,BagarovaJ,KerrG,et al.,2021.Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.JCI Insight,6(8):e95042.

[97]WittenMR,WuLX,LaiCT,et al.,2022.Inhibition of ALK2 with bicyclic pyridyllactams.Bioorg Med Chem Lett,55:128452.

[98]XiongHY,VeeduRN,DiermeierSD,2021.Recent advances in oligonucleotide therapeutics in oncology.Int J Mol Sciences,22(7):3295.

[99]YamamotoH,SakaiN,OhteS,et al.,2021.Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.Bioorg Med Chem Lett,38:127858.

[100]YamamotoM,StoesselSJ,YamamotoS,et al.,2022.Overexpression of wild‐type ACVR1 in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification.J Bone Miner Res,37(11):2077-2093.

[101]YamazakiH,OhteS,RotinsuluH,et al.,2020.Screening for small molecule inhibitors of BMP-induced osteoblastic differentiation from indonesian marine invertebrates.Mar Drugs,18(12):606.

[102]YangJW,KitamiM,PanHC,et al.,2021.Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β‍-catenin degradation.Sci Signal,14(665):eaaz9368.

[103]YangYS,KimJM,XieJ,et al.,2022.Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery.Nat Commun,13:6175.

[104]YangYS,LinCJ,MaH,et al.,2023.AAV-mediated targeting of the activin A-ACVR1^R206H signaling in fibrodysplasia ossificans progressiva.Biomolecules,13(9):1364.

[105]YeZQ,WangSY,ShanC,et al.,2023.The serum levels of activin A and bone morphogenetic protein-4 and-6 in patients with fibrodysplasia ossificans progressiva.Orphanet J Rare Dis,18:111.

[106]YuPB,DengDY,LaiCS,et al.,2008a.BMP type I receptor inhibition reduces heterotopic ossification.Nat Med,14(12):1363-1369.

[107]YuPB,HongCC,SachidanandanC,et al.,2008b.Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.Nat Chem Biol,4(1):33-41.

[108]ZhangYE,2017.Non-Smad signaling pathways of the TGF-‍β family.Cold Spring Harb Perspect Biol,9(2):a022129.

[109]ZitvogelL,RusakiewiczS,RoutyB,et al.,2016.Immunological off-target effects of imatinib.Nat Rev Clin Oncol,13(7):431-446.